Breast cancer is a heterogeneous disease which develops as a consequence of a combination of inherited germline and acquired somatic mutations. While some recent progress has been made in the development of chemotherapeutics which target specific oncogenic pathways, the reality is that most patients with advanced tumors will succumb to their disease. Two obstacles limit the effectiveness of current therapies: the ability to identify subpopulations of patients who are most likely to respond to a particular therapy and the development of rational combinations of therapies that can match the complexities of the tumor. Using a genomics based approach we have identified ten homogeneous breast cancer subtypes which are defined on the basis of altered oncogene and tumor suppressor activity. Additional analysis demonstrates that these subtypes are unique with regard to survival prognosis, age of disease onset, lymph node status and family history. The research proposed in this application will investigate the hypothesis that homogeneous breast cancer subtypes identified on the basis of altered pathway activity can be used to design personalized, and thus more effective, therapeutic regimens based on patterns of pathway activation. Furthermore, it is expected that the development of classes of breast tumor defined on the basis of homogenous patterns of oncogene and tumor suppressor pathway activity will enable the investigation of mechanisms of tumorigenesis for each subtype. This hypothesis will be addressed by experiments detailed in two specific aims: (1) characterization of breast tumors on the basis of pathway dysregulation and (2) use of genomic signatures to develop in vivo strategies for targeted breast cancer regimens. PUBLIC HEALTH RELEVANCE: The research described in this proposal will allow for the development of directed, individualized therapeutic strategies for breast cancer patients that will result in enhanced tumor response rates to individual and combination therapies;the ability to decrease cytotoxic side-effects;and the ability to limit the development of chemotherapeutic resistance. It is expected that these studies will result in a more complete understanding of pathway co-deregulation between breast tumor subtypes and will enable the comparison of pathway deregulation and clinical disease characteristics between breast tumors and other types and subtypes of tumors. Finally, analysis of pathway activity is likely to provide biological insight into pathways and genes responsible for characteristics of breast cancer subtypes which may result in the identification of novel therapeutic targets.